PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1 alpha activity. We found that PBRM1 is required for HIF-1 alpha transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1 alpha mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1 alpha mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1 alpha mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1 alpha mRNA and reduction of YTHDF2 results in reduced HIF-1 alpha protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1 alpha mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.